Neuropathology in cognitively impaired elderly individuals is commonly multifactorial, including Alzheimer type pathology, ischemic/vascular lesions, Lewy bodies, hippocampal sclerosis and TDP-43 proteinopathy. Recently, the latter two have shown to be linked. TDP-43 is the major protein that accumulates in neuronal inclusions in frontotemporal degeneration with ubiquitinated inclusions (FTLD-U) and in amyotrophic lateral sclerosis (ALS), but it is also detected in other disorders that show no obvious relationship to FTLD-U or ALS, suggesting alternative mechanisms for TDP-43 pathology. Mutations in the gene for progranulin {GRH) cause FTLD-U with hippocampal sclerosis, and almost all mutations are mediated by decreases in progranulin expression. The undeniable fact from these observations is that even partial decreases in progranulin over time lead to severe neurologic consequences. In cell culture studies, decreases in progranulin induce apoptosis, caspase-mediated TDP-43 cleavage and TDP-43 inclusions. Common variants in miRNA binding sites in the 3'UTR of GRN have been shown to increase the risk of FTLD-U through decreased progranulin expression; the same genetic variants predispose to hippocampal sclerosis. The goals of this proposal are to investigate these phenomena and there relationship to glucocorticoid mediated stress. The underlying hypothesis is that decreased progranulin expression, due to genetic or environmental factors or both, predisposes to neurodegeneration, particularly in the hippocampus. We hypothesize that deficiencies in progranulin predispose to hippocampal sclerosis. To address this hypothesis, studies are proposed in human autopsy tissue and in a mouse model of progranulin deficiency. In humans we will determine GR/V genotype and levels of progranulin in brains of individuals with and without hippocampal sclerosis. We hypothesize that hippocampal sclerosis will be associated with programed cell death that leads to TDP-43 pathology. To this end we will study TDP-43 pathology in hippocampal sclerosis with respect to markers of programmed cell death, as well as other possible stressors such as hypoxia, microvascular pathology and glucocorticoid stress. The animal studies will subject progranulin knockout mice and controls to glucocorticoid-mediated stress (physical restraint) to see if hippocampal pathology is greater in progranulin deficient animals. Similar experiments will be conducted in progranulin knock-out mice that have been crossbred with TDP-43 transgenic mice.